Choosing a Skeletal Muscle Relaxant Sharon See, Pharmd, BCPS, and Regina Ginzburg, Pharmd St

Home , Metaxalone, Methocarbamol, Muscle relaxant, Tizanidine

Choosing a Skeletal Muscle Relaxant Sharon See, PharmD, BCPS, and Regina Ginzburg, PharmD St. John’s University College of Pharmacy and Allied Health Professions, Jamaica, New York

Skeletal muscle relaxants are widely used in treating musculoskeletal conditions. However, evidence of their effectiveness consists mainly of studies with poor methodologic design. In addition, these drugs have not been proven to be superior to acetaminophen or nonsteroidal anti-inflammatory drugs for low back pain. Systematic reviews and meta-analyses support using skeletal muscle relaxants for short-term relief of acute low back pain when nonsteroidal anti-inflammatory drugs or acetaminophen are not effective or tolerated. Comparison studies have not shown one skeletal muscle relaxant to be superior to another. Cyclobenzaprine is the most heavily studied and has been shown to be effective for various musculoskeletal conditions. The sedative properties of tizanidine and cyclobenzaprine may benefit patients with insomnia caused by severe muscle spasms. Methocarbamol and metaxalone are less sedating, although effectiveness evidence is limited. Adverse effects, particularly dizziness and drowsiness, are consistently reported with all skeletal muscle relaxants. The potential adverse effects should be communicated clearly to the patient. Because of limited comparable effectiveness data, choice of agent should be based on side-effect profile, patient preference, abuse potential, and possible drug interactions. (Am Fam Physician. 2008;78(3):365-370. Copyright © 2008 American Acad- emy of Family Physicians.)

keletal muscle relaxants are often conditions. The American Pain Society and prescribed for musculoskeletal con- the American College of Physicians recom- ditions including low back pain, neck mend using acetaminophen and nonsteroi- pain, fibromyalgia, tension head- dal anti-inflammatory drugs (NSAIDs) as S aches, and myofascial pain syndrome. The first-line agents for acute low back pain and goals of treatment include managing muscle reserving skeletal muscle relaxants as an pain and improving functional status so the alternative treatment option.12 This recom- patient can return to work or resume previ- mendation is based on available literature, ous activities. which shows skeletal muscle relaxants are Skeletal muscle relaxants are divided into better than placebo, but not more effective two categories: antispastic (for conditions than nSAIDs in patients with acute back such as cerebral palsy and multiple sclero- pain. Similar recommendations exist in sis) and antispasmodic agents (for muscu- treating tension headaches.13 A meta-analysis loskeletal conditions). antispastic agents evaluating the use of cyclobenzaprine showed (e.g., baclofen [Lioresal], dantrolene [Dant- that, although this drug was better than pla- rium]) should not be prescribed for muscu- cebo for the treatment of fibromyalgia, it loskeletal conditions because there is sparse was considered inferior to antidepressants.14 evidence to support their use. rather, an Additionally, recent guidelines on fibromy- antispasmodic agent may be more appropri- algia recommend using a comprehensive ate (Table 1).1-9 approach that utilizes tramadol (Ultram), Among antispasmodic agents, cariso- antidepressants, and/or a heated pool (with prodol (Soma), cyclobenzaprine (Flexeril), or without exercise).15 metaxalone (Skelaxin), and methocarba- Prescription rates for nonspecific back mol (Robaxin) were among the top 200 pain revealed that skeletal muscle relaxants drugs dispensed in the united States in accounted for 18.5 percent of prescriptions 2006.10,11 Despite their popularity, skeletal compared with 16.3 percent for NSAIDs and muscle relaxants should not be the primary 10 percent for cyclooxygenase-2 inhibitors.16 drug class of choice for musculoskeletal Because of the high rate of prescribing skeletal

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Drug Recommended dosage Most common adverse effects Comments Monthly cost*

Carisoprodol 350 mg four times daily Dizziness, drowsiness, headache Physical or psychological dependence may occur; withdrawal symptoms may occur with $72 to $100 (generic) (Soma)1 Not recommended for children Rare idiosyncratic reactions (mental status changes, transient discontinuation $590 (brand) younger than 12 years quadriplegia, and temporary loss of vision) after first dose; may Possible respiratory depression when combined with benzodiazepines, barbiturates, codeine require hospitalization or its derivatives, or other muscle relaxants Allergy-type reactions may occur after the first to fourth dose; Contraindicated in acute intermittent porphyria may be mild (e.g., cutaneous rash) or more severe (e.g., asthma FDA pregnancy category C attack, angioneurotic edema, hypotension, or anaphylactic shock); antihistamines, epinephrine, or corticosteroids may be needed

Chlorzoxazone Adults: 250 to 750 mg three to four Dizziness, drowsiness Avoid use in patients with hepatic impairment 15 to 77 (generic) (Parafon Forte)2 times daily Red or orange urine Possible respiratory depression when combined with benzodiazepines, barbiturates, codeine 180 (brand) Children: 125 to 500 mg three to four GI irritation and rare GI bleeding or its derivatives, or other muscle relaxants times daily; or 20 mg per kg daily in Hepatoxicity (rare); discontinue with elevated liver function test FDA pregnancy category C three or four divided doses

Cyclobenzaprine 5 mg three times daily; may increase Anticholinergic effect (drowsiness, dry mouth, urinary retention, Most studied skeletal muscle relaxant 120 to 140 (generic) (Flexeril)3 to 10 mg three times daily increased intraocular pressure) Long elimination half-life 157 (brand) Rare but serious adverse effects are arrhythmias, seizures, 5-mg dose as effective as 10-mg, with fewer adverse effects myocardial infarction Avoid in older patients and in patients with glaucoma Possible drug interaction with CYP450 inhibitors Seizures reported with concomitant use of tramadol (Ultram); combination should be avoided in patients with medical conditions that may induce seizures Contraindicated in patients with arrhythmias, recent myocardial infarction, or congestive heart failure FDA pregnancy category B

Diazepam Adults: 2 to 10 mg three to four times Dizziness, drowsiness, confusion Also an antispastic agent 11 to 23 (generic) (Valium)4 daily Abuse potential Long elimination half-life; avoid in older patients and in patients with hepatic impairment 184 (brand) Children: 0.12 to 0.80 mg per kg daily Possible drug interaction with CYP450 inhibitors in three or four divided doses Complete blood count and liver function tests indicated for prolonged use FDA pregnancy category D; avoid especially in the first trimester

Metaxalone 800 mg three to four times daily Drowsiness, dizziness, headache, nervousness Use with caution in patients with liver failure 275; generic not available (Skelaxin)5 Not recommended in children younger Leukopenia or hemolytic anemia (rare) Possible respiratory depression when combined with benzodiazepines, barbiturates, codeine than 12 years Liver function test elevation (rare) or its derivatives, or other muscle relaxants Nausea, vomiting, and diarrhea (rare) Less dizziness and drowsiness than other skeletal muscle relaxants Paradoxical muscle cramps FDA pregnancy category C

Methocarbamol 1,500 mg four times daily for first two Black, brown, or green urine possible Possible respiratory depression when combined with benzodiazepines, barbiturates, codeine 15 to 58 (generic) (Robaxin)6 to three days, followed by 750 mg Mental status impairment or its derivatives, or other muscle relaxants 176 (brand) four times daily Possible exacerbation of myasthenia gravis symptoms FDA pregnancy category C; reports of fetal abnormalities

Orphenadrine 100 mg twice daily Anticholinergic effect (drowsiness, dry mouth, urinary retention, Long elimination half-life 110 to 140 (generic) (Norflex)7 Combination products are dosed three increased intraocular pressure) Reduced dosages in older patients 162 (brand) to four times daily Aplastic anemia (rare) Avoid in patients with glaucoma, cardiospasm, or myasthenia gravis GI irritation Decreases effect of phenothiazines (e.g., chlorpromazine [Thorazine†], promethazine [Phenergan]) Confusion, tachycardia, hypersensitivity reaction (with high doses) FDA pregnancy category C

Tizanidine 4 mg initially; may increase by 2 to Dose-related hypotension, sedation, and dry mouth Also antispastic agent 329 (generic) (Zanaflex)8,9 4 mg every six to eight hours until Hepatotoxicity; monitor liver function tests at baseline and one, Do not use with CYP1A2 inhibitors, ciprofloxacin (Cipro) or fluvoxamine (Luvox CR) 437 (brand) relief three, and six months Caution with CYP1A2 inhibitors, central nervous system depressants, or alcohol Do not exceed 36 mg daily Withdrawal and rebound hypertension may occur in patients Decreased effectiveness with oral contraceptives discontinuing therapy after receiving high doses for long period FDA pregnancy category C of time; tapering is recommended

NOTE: The table contains only selected highlights about these medications. All of these drugs may cause increased drowsiness with central nervous *—For the recommended adult dosage. Estimated cost to the pharmacist based on average wholesale prices (rounded to the nearest dollar) in Red Book. system depressants. Caution is advised when prescribing skeletal muscle relaxants in older patients. Montvale, N.J.: Medical Economics Data, 2007. Cost to the patient will be higher, depending on prescription filling fee. CYP = cytochrome P; FDA = U.S. Food and Drug Administration; GI = gastrointestinal. †—Brand not available in the United States. Information from references 1 through 9. Skeletal Muscle Relaxants Table 1. Skeletal Muscle Relaxants (Antispasmodic Agents)

Drug Recommended dosage Most common adverse effects Comments Monthly cost*

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Evidence Clinical recommendation rating References

Skeletal muscle relaxants are not considered first-line therapy for musculoskeletal conditions. C 12, 13, 15 Skeletal muscle relaxants may be used as adjunctive therapy for acute low back pain. B 17, 18 Antispasmodic agents should be used short-term (two weeks) for acute low back pain. C 17, 18 There is no clear evidence that one skeletal muscle relaxant is superior to another for B 17, 18 musculoskeletal spasms. Choice of skeletal muscle relaxant should be based on individual drug characteristics and C 32 patient situation.

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease- oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, see http://www.aafp. org/afpsort.xml. muscle relaxants, an understanding of the risks and benefits shown to improve pain, muscle spasm, functional status, of this class of drugs is vital. This article presents evidence and global evaluation versus diazepam (Valium) in two regarding the use of antispasmodic skeletal muscle relax- fair-quality studies.23,24 Conversely, two other fair- and ants for various musculoskeletal conditions, and appropri- poor-quality studies did not reveal any significant dif- ate drug selection if a skeletal muscle relaxant is required. ference between cyclobenzaprine and diazepam.25,26 One Highlights of contraindications, adverse effects, and drug meta-analysis evaluated 14 studies comparing cycloben- interactions for these drugs are listed in Table 1.1-9 zaprine with placebo for back and neck pain.27 The trials included were of less than 14 days’ duration. Cycloben- Evidence of Effectiveness zaprine was found to be moderately more effective than Many of the studies evaluating the effectiveness of skel- placebo, but had more central nervous system adverse etal muscle relaxants are hampered by poor methodologic effects. The authors also described several limitations of design, including incomplete reporting of compliance, the meta-analysis including inadequate blinding, hetero- improper or no mention of allocation concealment, not geneity among studies, and the presence of publication utilizing intention-to-treat methods, and inadequate ran- bias.27 Overall, studies appear to be consistent, with cyclo- domization.17,18 Nonetheless, skeletal muscle relaxants have benzaprine having greatest benefit within the first few been evaluated in systematic reviews and meta-analyses. days of treatment rather than at one or two weeks.18,27 Skeletal muscle relaxants have also been studied as Back and Neck Pain adjunctive therapy to analgesics in treating acute low back Some evidence appears to support nonbenzodiazepine pain. In one open-label study (20 patients), the addition of skeletal muscle relaxants, such as carisoprodol, cyclo- cyclobenzaprine to naproxen (Naprosyn) resulted in a sta- benzaprine, orphenadrine (Norflex), and tizanidine tistically significant decrease in muscle spasm and tender- (Zanaflex), for acute low back pain.17,18 These agents ness compared with naproxen alone.28 A Cochrane review have been shown to be moderately effective for short- analyzed three high-quality trials (560 total patients) that term relief (two weeks) compared with placebo.17,18 Ran- showed tizanidine plus analgesics was more effective in domized controlled trials involving metaxalone have providing pain relief and decreasing muscle spasm than not been conducted since the 1970s. one fair-quality analgesics alone.17 Conversely, one low-quality open-label study showed no difference between metaxalone and study (867 patients) comparing cyclobenzaprine alone placebo.19 Limited evidence exists to support the use of (5 mg three times daily) versus combination with ibuprofen skeletal muscle relaxants in chronic low back pain.17,20 (Motrin; either 400 or 800 mg three times daily) showed Benzodiazepines have been effective for short-term use that, although all groups improved at seven days, there was compared with placebo, but the basis of this recommen- no statistical difference in outcomes among the groups.29 dation stemmed from trials involving tetrazepam, which Nonetheless, the use of combination therapy has been is not available in the United States.21,22 supported in quickening recovery,17 with minimal Cyclobenzaprine has been the most heavily studied overall risk of adverse effects (relative risk [RR] = 1.34; drug, with consistently proven effectiveness.17,18 it was 95% confidence interval [CI], 0.67 to 2.67].20

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Fibromyalgia short-term use; therefore, multiple modalities (e.g., phys- Cyclobenzaprine has also been studied in treating fibro- ical therapy, adjunctive analgesics) may be warranted to myalgia. A meta-analysis of five trials ranging from six prevent chronic use of these medications. to 24 weeks’ duration included a total of 312 patients Selection of a skeletal muscle relaxant should be with fibromyalgia. The authors reported that, although individualized to the patient. if there are tender spots cyclobenzaprine moderately improved sleep and pain, over the muscle or trigger points on physical examina- the long-term benefits were unknown. This meta- tion, a skeletal muscle relaxant is a reasonable adjunct analysis was limited by a high drop-out rate, short trial to analgesic treatment of low back pain. Skeletal muscle duration, few studies having an intention-to-treat design, relaxants may also be used as an alternative to NSAIDs and inadequate blinding.14 in patients who are at risk of gastrointestinal or renal complications. Comparison Data Patients with low back pain or fibromyalgia may bene Strong data comparing skeletal muscle relaxants to each fit from treatment with cyclobenzaprine. Recent evidence other are scarce. a systematic review evaluated 46 tri- showed similar effectiveness at half of its manufacturer rec- als (head-to-head and placebo-controlled) comprising ommended dose (5 mg), but with fewer adverse effects.33 It mostly of studies on low back pain or neck syndromes. may optimally be used in younger patients with limited or The placebo-controlled trials included 17 on cyclobenza- no medical conditions. Higher doses of cyclobenzaprine prine, six on tizanidine, four on carisoprodol, and four or tizanidine would be appropriate to promote sedation on orphenadrine, and were mostly conducted more than in cases of more severe discomfort or perceived muscu- 15 years ago. The average patient enrollment was less than lar spasm. Although there appears to be insufficient data 150 patients (range 12 to 400 patients). In general, all of the on metaxalone and methocarbamol, these may be useful drugs were shown to have some benefit.18 The limitations in patients who cannot tolerate the sedative properties of of published comparison trials include using unvalidated cyclobenzaprine or tizanidine. Of note, methocarbamol scales to measure outcomes, involving small numbers of costs substantially less than metaxalone. participants, and often not reporting adverse effects of Carisoprodol is metabolized to meprobamate (a class studied medications. One fair-quality study showed cari- III controlled substance) and has been shown to produce soprodol was better than diazepam at improving muscle psychological and physical dependence.34 Carisoprodol spasm and global and functional status in patients with and diazepam should be reserved for last-line therapy low back pain.30 another fair-quality study comparing because of their abuse potential and lack of superiority tizanidine with chlorzoxazone (Parafon Forte) for back to other skeletal muscle relaxants. Although all skeletal spasms did not show any significant difference.31 muscle relaxants should be used with caution in older A different systematic review did include some studies patients, diazepam especially should be avoided in older which were considered to be high quality.17 These studies patients or in patients with significant cognitive or revealed no difference in outcomes (e.g., muscle spasms, hepatic impairment. muscle pain, tension, tenderness, functional status) This is one in a series of “Clinical Pharmacology” articles coordinated by among cyclobenzaprine versus carisoprodol; chlorzoxa- Allen F. Shaugnessy, PharmD, Tufts University Family Medicine Residency zone versus tizanidine; or diazepam versus tizanidine.17 at Cambridge Health Alliance, Malden, Mass.

Place in Therapy The Authors Although the evidence for effectiveness of skeletal muscle relaxants in musculoskeletal conditions is limited, sharon see, PharmD, BCPS, is an associate clinical professor at St. John’s strong evidence does exist in terms of toxicity. In acute University College of Pharmacy and Allied Health Professions in Jamaica, NY, and a faculty member at the Beth Israel Residency Program in Urban low back pain trials, skeletal muscle relaxants increased Family Practice in New York, NY. She received her doctor of pharmacy overall adverse effects (RR = 1.50; 95% CI, 1.14 to 1.98) degree from Rutgers University College of Pharmacy in New Brunswick, NJ, and central nervous system adverse effects (RR = 2.04; and completed an inpatient family medicine pharmacy specialty residency at 95% CI, 1.23 to 3.37) such as dizziness and drowsiness.17 Deaconess Hospital and the St. Louis College of Pharmacy in St. Louis, Mo. Because of the weak evidence for comparable effective- REGINA Ginzburg, PharmD, is an assistant clinical professor at St. John’s ness, selection of an agent should be based on side-effect University College of Pharmacy and Allied Health Professions and a faculty profile, patient preference, abuse potential, drug interac- member at the Beth Israel Residency Program in Urban Family Practice. She received her doctor of pharmacy degree from St. John’s University Col- tion potential, and other characteristics of the individ- lege of Pharmacy and Allied Health Professions, and completed a general ual drugs.32 Skeletal muscle relaxants are indicated for practice residency at Albert Einstein Medical Center in Philadelphia, Pa.

August 1, 2008 ◆ Volume 78, Number 3 www.aafp.org/afp American Family Physician 369 Skeletal Muscle Relaxants

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